Medicine chapters
Hepatic encephalopathy and drugs to avoid in liver disease
Why liver failure affects the brain, the triggers and grades of hepatic encephalopathy, treatment with lactulose and rifaximin, and which drugs to avoid or use with care in patients with liver disease.
- Hepatic encephalopathy is brain dysfunction from gut-derived toxins, mainly ammonia, that bypass a failing or shunted liver; astrocytes swell as they turn ammonia into glutamine.
- Look first for a precipitant: GI bleed, infection (SBP), constipation, sedatives, electrolyte upset from diuretics, dehydration or a TIPS.
- Treat the trigger, give lactulose (aim for 2–3 soft stools a day) and add rifaximin to prevent recurrence; avoid sedatives, opioids, NSAIDs, ACE inhibitors and nephrotoxins in liver disease.
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Overview
Hepatic encephalopathy (HE), also called portosystemic encephalopathy, is a reversible neuropsychiatric syndrome caused by liver failure and/or blood bypassing the liver (portosystemic shunting). It ranges from subtle slowing of thought to deep coma.
It may occur in acute liver failure (with a risk of cerebral oedema), in cirrhosis (the usual exam scenario), or after shunts such as TIPS. An episode of overt HE is a sign of advanced disease and a reason to consider liver transplant.
Pathophysiology
- Gut bacteria break down protein (food or blood in the gut) to make ammonia and other nitrogenous toxins.
- Normally the liver clears ammonia into urea. In cirrhosis, portal blood bypasses the liver through collaterals or shunts, and failing liver cells clear less.
- In the brain, astrocytes detoxify ammonia by joining it to glutamate to make glutamine. Glutamine pulls water in and the astrocytes swell. Histology shows Alzheimer type II astrocytes.
- Other contributors: increased GABA-like inhibitory tone, false neurotransmitters (octopamine), mercaptans, raised aromatic and reduced branched-chain amino acids, inflammation and infection.
The leading mechanism is ammonia acting at the astrocyte, but blood ammonia level does not match severity well. HE is a clinical diagnosis.
Precipitating factors
| Category | Examples |
|---|---|
| Extra nitrogen load | Upper GI bleeding (blood is a protein meal), high-protein meal, constipation |
| Infection | Spontaneous bacterial peritonitis, urinary or chest infection |
| Drugs | Sedatives (benzodiazepines), opioids, alcohol |
| Fluid and electrolytes | Over-diuresis, large-volume paracentesis, vomiting, hypokalaemia and alkalosis (raise kidney ammonia output), hyponatraemia, dehydration |
| Shunting | TIPS or surgical shunts, spontaneous large shunts |
| Other | Surgery, kidney injury, hypoglycaemia, hypoxia, development of HCC, portal vein thrombosis, worsening liver damage |
Triggers are the "4 Cs and Bs": Constipation, Chemicals (sedatives), Calories/protein excess, Contagion (infection); Bleeding, Bypass (TIPS), Body salts (electrolytes).
In a stable cirrhotic who becomes drowsy with a flap, look for infection, a GI bleed and constipation first, and do a diagnostic ascitic tap.
Clinical features
- Chronic or subtle: changes in personality, mood and intellect; poor concentration; reversal of the sleep-wake cycle (sleepy by day, awake at night).
- Acute: increasing confusion, drowsiness, then coma.
- Signs:
- Asterixis (flapping tremor): with arms outstretched and wrists extended, the hands show irregular jerky flapping. It is a negative myoclonus (brief loss of posture).
- Fetor hepaticus: sweet, musty breath.
- Constructional apraxia: cannot copy a five-pointed star or draw a clock.
- Slow, slurred speech; increased tone, hyper-reflexia; plantars may become extensor in coma.
- Seizures are rare; if present, look for another cause.
Asterixis is not specific to liver failure. It also occurs in uraemia and CO2 retention.
Grading (West Haven)
| Grade | Features |
|---|---|
| Minimal (covert) | No obvious signs; abnormal psychometric tests (number connection, serial sevens); impaired driving |
| I | Mild confusion, short attention span, anxiety or euphoria, sleep reversal |
| II | Drowsy, disoriented in time, inappropriate behaviour, obvious asterixis |
| III | Stuporous but rousable, marked confusion, incoherent speech |
| IV | Coma, unresponsive to pain |
Investigations
The diagnosis is clinical. Tests look for the precipitant and exclude other causes.
- Blood glucose at once (hypoglycaemia mimics or worsens HE).
- Full blood count, urea and electrolytes (potassium, sodium, creatinine), liver tests, INR, CRP.
- Diagnostic ascitic tap (SBP), blood and urine cultures, chest X-ray.
- Look for GI bleeding (melaena on rectal examination, falling Hb, raised urea).
- Arterial ammonia: supportive and helps in unexplained coma; a normal level makes HE less likely.
- EEG: slowing of the normal alpha rhythm, often with triphasic waves.
- CT head if there is a fall, focal signs or no response to treatment, especially in drinkers (subdural haematoma).
Differential diagnosis
Hypoglycaemia, Wernicke encephalopathy (give thiamine), alcohol intoxication or withdrawal (delirium tremens), subdural haematoma, sepsis, hyponatraemia, drug overdose, uraemia, meningitis, stroke.
Management
Acute episode
- ABC: grade III–IV patients may need airway protection and ICU care. Nurse at 30 degrees; check glucose.
- Find and treat the precipitant: stop sedatives and diuretics, correct potassium and fluid, treat infection, manage bleeding, relieve constipation.
- Lactulose: Kumar gives 10–30 mL three times daily; adjust to produce 2–3 soft stools a day. In drowsy patients give it by nasogastric tube or as an enema.
- Antibiotics: rifaximin (poorly absorbed, few side effects) is used, especially to prevent recurrence. Metronidazole for short courses is an option; neomycin is avoided (kidney and ear toxicity).
- Nutrition: any protein restriction should last 48 hours at most; feed normally (by fine-bore NG tube if needed) and increase protein as the patient improves. Vegetable and dairy protein are better tolerated.
- IV fluids with care about sodium load; correct hypokalaemia.
- Thiamine IV in drinkers before glucose.
How lactulose works
Lactulose is a synthetic sugar that is not absorbed. Colonic bacteria ferment it to acids, so the colonic pH falls. Ammonia (NH3) is converted to ammonium (NH4+), which cannot cross back into blood, and it is passed in the stool. Lactulose also acts as an osmotic laxative, shortening transit and changing the gut flora away from ammonia-producing bacteria. Lactitol works similarly.
After a first episode, continue lactulose. If HE recurs despite lactulose, add rifaximin (secondary prevention).
Longer term
- Avoid triggers; keep bowels regular.
- Consider embolising large spontaneous shunts or reducing a TIPS in selected patients.
- Liver transplant assessment after an episode of overt HE.
- Advise against driving while affected.
Drugs to avoid or use with care in liver disease
Why liver disease changes drug handling
- Reduced metabolism by damaged liver cells: drug effects last longer.
- Portosystemic shunting bypasses first-pass metabolism, so drugs normally cleared by the liver on first pass (for example morphine, propranolol, lidocaine) reach higher blood levels.
- Low albumin leaves more unbound active drug; bilirubin competes for binding sites.
- Cholestasis reduces clearance of drugs excreted in bile.
- The diseased patient is also more sensitive: sedatives tip them into HE; NSAIDs cause bleeding and kidney failure; salt-containing drugs worsen ascites.
Key drugs
| Drug or group | Problem in liver disease | What to do |
|---|---|---|
| Benzodiazepines, opioids, codeine, antihistamine sedatives | Precipitate encephalopathy and coma | Avoid; if essential use small doses. For alcohol withdrawal, lorazepam or oxazepam (short-acting) rather than chlordiazepoxide, whose half-life lengthens |
| NSAIDs and aspirin | GI bleeding (with low platelets and clotting factors), sodium retention, renal failure / hepatorenal syndrome, blunt diuretics | Avoid; use paracetamol at a reduced daily dose |
| ACE inhibitors and angiotensin receptor blockers | Lower blood pressure and kidney perfusion → renal failure | Avoid in ascites |
| Aminoglycosides and other nephrotoxins, IV contrast | Kidney injury; HRS | Avoid if possible; use alternatives |
| Diuretics in excess | Hypokalaemia, hyponatraemia, dehydration → HE and kidney injury | Monitor closely; stop if sodium or creatinine worsen |
| Constipating drugs (opioids, anticholinergics) | Constipation precipitates HE | Avoid or give lactulose |
| Sodium-rich preparations (effervescent or soluble tablets, some antacids, some IV antibiotics) | Worsen ascites and oedema | Choose low-sodium forms |
| Metformin | Lactic acidosis in advanced liver failure | Avoid in decompensated disease |
| Sulphonylureas, insulin | Hypoglycaemia (poor gluconeogenesis) | Lower doses, careful monitoring |
| Warfarin | Exaggerated effect; INR already high | Avoid unless clearly indicated; monitor |
| Hepatotoxic drugs (methotrexate, isoniazid, valproate, high-dose tetracyclines) | Further liver injury | Avoid or monitor liver tests closely |
| Oestrogens and the combined pill | Cholestasis; Budd-Chiari risk | Avoid in active liver disease |
| Chloramphenicol, pethidine | Accumulate | Avoid |
In cirrhosis, the classic trio to avoid is sedatives (encephalopathy), NSAIDs (bleeding and renal failure) and ACE inhibitors (renal failure).
Paracetamol is not banned in liver disease. At a reduced total daily dose it is the safest simple analgesic. NSAIDs are the dangerous choice.
Expect: role of ammonia and astrocyte swelling (glutamine); Alzheimer type II astrocytes; precipitants (GI bleed, infection/SBP, constipation, sedatives, diuretics, hypokalaemia, TIPS); asterixis and constructional apraxia; West Haven grades; EEG triphasic waves; how lactulose works; rifaximin for recurrence; no prolonged protein restriction; neomycin avoided; why sedatives, opioids, NSAIDs and ACE inhibitors are avoided; paracetamol at a reduced dose as the safest analgesic; short-acting benzodiazepines (lorazepam, oxazepam) for withdrawal.
Quick revision
- HE = gut toxins (ammonia) bypass the liver; astrocytes swell from glutamine.
- Triggers: bleed, infection, constipation, sedatives, diuretics/electrolytes, TIPS.
- Asterixis, fetor, constructional apraxia, sleep reversal; seizures are rare.
- Grades I–IV: confused → drowsy with flap → stupor → coma.
- Diagnosis is clinical; check glucose, tap ascites, look for bleeding.
- Lactulose to 2–3 soft stools a day; add rifaximin for recurrence; avoid neomycin.
- Do not restrict protein beyond 48 hours.
- Avoid sedatives, opioids, NSAIDs, ACE inhibitors, nephrotoxins and high-sodium drugs.
- Paracetamol at a reduced dose is the safest painkiller.
Written by The House Job from standard references (Kumar and Clark's Clinical Medicine).
FAQ
How does lactulose help in hepatic encephalopathy?
It is fermented in the colon to acids, which turn ammonia into ammonium that cannot be absorbed, and its laxative action clears nitrogen-rich contents from the bowel.
Should protein be stopped in hepatic encephalopathy?
No. Protein can be reduced for up to about 48 hours in severe cases, but malnutrition worsens outcome, so normal protein intake should be restored quickly.
Why are NSAIDs dangerous in cirrhosis?
They increase the risk of bleeding from varices and ulcers, cause salt and water retention, and can trigger renal failure including hepatorenal syndrome.
What is the most important first step in a cirrhotic patient with new confusion?
Check blood glucose and look for a precipitant, especially infection (with an ascitic tap), gastrointestinal bleeding, constipation and sedative drugs.